What is nivolumab?
Nivolumab (OPDIVO®, Bristol Myers Squibb, New Jersey, USA) is a human programmed death receptor-1 (PD-1)-blocking antibody, approved in Japan and the USA for treatment of advanced melanoma.
What is nivolumab used for?
In December 2014, the US Food and Drug Administration (FDA) approved the use of nivolumab in:
- Patients with unresectable or metastatic melanoma and disease progression after treatment with ipilimumab (Yervoy®)
- BRAF V600 mutation positive melanoma patients with disease progression despite treatment with ipilimumab and a BRAF inhibitor (eg vemurafenib or dabrafenib).
In October 2015, nivolumab was approved for use in combination with ipilimumab for improved response in advanced melanoma (unresectable or metastatic disease). In January 2016, it was also approved in untreated BRAF-wild type melanoma.
In the European Union, the European Medicines Agency (EMA) has validated for review the Marketing Authorization Application for Nivolumab in advanced melanoma. The application has also been granted accelerated assessment by the EMA’s CHMP (Committee for Medicinal Products for Human Use). Nivolumab is available in New Zealand, and funded by PHARMAC for some cases of metastatic and unresectable advanced melanoma.
How does nivolumab work?
- The PD-1 pathway serves as a checkpoint to limit T-cell–mediated immune responses.
- Cancer cells may exploit “regulatory” pathways, such as checkpoint pathways, to hide from the immune system and shield the tumour from immune attack.
- Both PD-1 ligands, PD-L1 (programmed death receptor ligand 1) and PD-L2, engage the PD-1 receptor and induce PD-1 signaling and associated T-cell “exhaustion,” a reversible inhibition of T-cell activation and proliferation.
- PD-L1/PD-1 interaction inhibits immune activation and reduces T-cell cytotoxic activity when bound.
- This negative feedback loop is essential for maintaining normal immune responses and limits T-cell activity to protect normal cells during chronic inflammation.
- Tumour cells may circumvent T-cell–mediated cytotoxicity by expressing PD-L1 on the tumour itself or on tumour-infiltrating immune cells, resulting in the inhibition of immune-mediated killing of tumour cells.
- Abnormal PD-L1 expression on the surface of melanoma cells activates PD-1 and suppresses cytotoxic T-cell activity.
- This T-cell tolerance enables the tumour cells to avoid recognition and attack by the immune system.
- Nivolumab is a highly selective humanised monoclonal IgG4 antibody that binds to the checkpoint receptor PD-1 on activated T cells and blocks its interaction with PD-L1 and PD-L2, releasing the PD-1 pathway-mediated inhibition of immune response against tumour cells.
How is nivolumab administered?
- Nivolumab is administered intravenously at a dose of 3 mg/kg every 2 weeks and infused over 1 hr.
- Treatment is continued until disease progression or unacceptable toxicity.
- Hypothyroidism or hyperthyroidism: no recommended dose modifications
- Renal impairment: no dosage modifications are required
- Mild hepatic impairment: no dosage modifications required
- Moderate or severe hepatic impairment: no studies are available.
Withhold medication for any of the following conditions
- Grade 2 pneumonitis
- Grade 2 or 3 colitis
- AST or ALT >3-5 x upper normal limit (UNL) or total bilirubin >1.5-3 x UNL
- Serum creatinine >1.5-6 x UNL or >1.5 times baseline
- Any other severe or grade 3 treatment-related adverse reactions
- Treatment may be resumed in patients whose adverse reactions recover to grade 0–1
Permanently discontinue in any of the following conditions
- Any life-threatening or grade 4 adverse reactions
- Grade 3 or 4 pneumonitis
- Grade 4 colitis
- AST or ALT >5 x UNL or total bilirubin >3 x UNL
- Serum creatinine >6 x UNL
- Any severe or grade 3 treatment-related adverse reaction that recurs
- Inability to reduce corticosteroid dose to ≤10 mg/day of prednisone or equivalent within 12 weeks
- Persistent grade 2 or 3 treatment-related adverse reactions that do not recover to grade 0–1 within 12 weeks after the last dose
Potential drug interactions with nivolumab
No formal pharmacokinetic drug-drug interaction studies have been conducted with nivolumab.
What are the adverse effects of nivolumab?
- In clinical trials the following adverse events have been observed at an incidence >10%: increased alanine aminotransferase (28%), hyponatraemia (25%), increased alkaline phosphatase (22%), rash (21%), pruritus (19%), cough (17%), increased ALT (16%), hyperkalaemia (15%), upper respiratory tract infection (11%).
Other clinically important adverse events occurring at an incidence of 1–10% have included:
- Cardiac disorders: ventricular arrhythmia
- Eye disorders: iridocyclitis
- Infusion-related reactions
- Immune-mediated disorders: severe pneumonitis or interstitial lung disease, colitis, hepatitis, nephritis and thyroid disorders
A clinical trial of the combination of nivolumab and ipilimumab had 36% dropout due to side effects, mainly diarrhoea and elevated liver function tests.
Cutaneous adverse effects of nivolumab
Skin complications are common in patients treated with nivolumab, with about 40% of patients experiencing these, with mean onset of rash being about 10 months into the course of treatment. Reported reactions include:
- Morbilliform eruption
- Lichenoid eruption
- Vitiligo and poliosis (whitening of hair)
- Bullous pemphigoid
- Sarcoid-like granuloma
Darkening of hair has been reported in a few patients taking PD-1 inhibitors for non-small cell lung cancer .
Use of nivolumab in pregnancy
- The incidences of malformations and pregnancy loss in human pregnancies have not been established for nivolumab.
- Nivolumab should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- In animal reproduction studies, administration to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature fetal death.
- Human IgG4 is known to cross the placental barrier and nivolumab is an IgG4; therefore, nivolumab has the potential to be transmitted from the mother to the developing fetus.
- The effects of nivolumab are likely to be greater during the second and third trimesters of pregnancy; there are no available human data informing the drug-associated risk.
Use of nivolumab in nursing mothers
- It is not known whether nivolumab or its metabolites are present in human milk.
- Advise women to discontinue breastfeeding during treatment.
Paediatric use of nivolumab
The safety and effectiveness of nivolumab has not been established in paediatric patients.
Geriatric use of nivolumab
Clinical studies of nivolumab did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients.
Renal impairment and nivolumab
Based on a population pharmacokinetic analysis, no dose adjustment is recommended in patients with renal impairment.
Hepatic impairment and nivolumab
Based on a population pharmacokinetic analysis, no dose adjustment is recommended for patients with mild hepatic impairment. Nivolumab has not been studied in patients with moderate or severe hepatic impairment.